Study on one-pot four-component synthesis of 9-aryl-hexahydro-acridine-1,8- diones using SiO2-I as a new heterogeneous catalyst and their anticancer activity

Article abstract of DOI:10.1016/j.bmcl.2014.06.047

A simple, efficient and cost-effective method for the synthesis of 9-aryl-hexahydro-acridine-1,8-diones by a one-pot four-component cyclocondensation of dimedone, aromatic aldehydes and ammonium acetate as a nitrogen source in the presence of a new hetero

Full text of DOI:10.1016/j.bmcl.2014.06.047

Bioorganic & Medicinal Chemistry Letters 24 (2014) 3907–3913
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Study on one-pot four-component synthesis of 9-aryl-hexahydro-
acridine-1,8-diones using SiO2–I as a new heterogeneous catalyst and
their anticancer activity
⇑
K. B. Ramesh, M. A. Pasha
Department of Studies in Chemistry, Central College Campus, Palace Road, Bangalore University, Bengaluru 560001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 January 2014
Revised 3 June 2014
Accepted 17 June 2014
Available online 25 June 2014
A simple, efficient and cost-effective method for the synthesis of 9-aryl-hexahydro-acridine-1,8-diones
by a one-pot four-component cyclocondensation of dimedone, aromatic aldehydes and ammonium ace-
tate as a nitrogen source in the presence of a new heterogeneous catalyst silica iodide (SiO2–I) in EtOH at
80 °C is described. SiO2–I was subjected to SEM–EDX and found to have iodo group bound to the catalyst.
Some of the prepared acridine-diones were found to exhibit promising anti-cancer activity against HepG2
and MCF-7 cell lines.
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
9-Aryl-hexahydro-acridine-1,8-diones
Aromatic aldehydes
Dimedone
Ammonium acetate
Silica iodide
Anticancer activity
Multicomponent reactions (MCRs) have emerged as efficient
and powerful strategies in the modern synthetic organic chemistry
because synthesis of complex organic molecules from simple and
readily available substrates can be achieved in a very fast and effi-
cient manner without the isolation of any intermediates.1 MCRs
contribute to the requirements of an environment friendly process
by reducing the number of synthetic steps, energy consumption
and waste production.2 Therefore, developing new MCRs and
improvement of known MCRs are popular areas of research in
the current synthetic organic chemistry. MCRs play a major role
in several biological processes and proliferation of cancer cells.3
Cancer is one of the lethal diseases which can lead to human death.
In most of the cases multi-drug resistance generally leads to the
failure of chemotherapy; and most of the drugs used for the treat-
ment of cancer are cytotoxic drugs which lack the site specific
activity to cancer cells and lead to damage of the healthy cells.
Many research groups have shown anticancer activity of different
acridine analogs (Fig. 1), including compounds 1 and 2 on cancer
cells.4
Acridines are an important class of organic compounds which
find use as dyes, fluorescent materials for visualization of biomol-
ecules, and in laser technology due to their useful spectroscopic
properties.7 Acridines have also received significant attention from
many pharmaceutical and organic chemists, essentially because of
the broad spectrum of their biological and pharmaceutical proper-
ties, such as: antiviral,8 antibacterial,9 anti-nociceptive activities,10
as well as efficiency in photodynamic therapy11 and because of the
anti-inflammatory activity.12 There are a few reports in the litera-
ture on the three-component Hantzsch-type condensation of
aromatic aldehydes, anilines and dimedone via the traditional
heating in organic solvents13,14 under microwave irradiation15
and in ionic liquids16,17 leading to acridines. The main drawback
of these methods is the inability to synthesize 9-aryl-hexahydro-
acridine-1,8-diones, therefore, the development of simple,
efficient, high-yielding and environment friendly methods and
use of simple, readily available, recyclable, new heterogeneous
catalysts for the preparation of acridines under mild conditions is
in demand.
Derivatives of acridine 3 and 4 (Fig. 2) showed good cytotoxic
In recent years, the heterogeneous catalysis has developed con-
siderable interest in the various disciplines of science including
organic synthesis due to the prime advantage that, in most of the
cases the heterogeneous catalysts can be recovered with only
minor change in activity and selectivity so that they can be used
in continuous flow reactions.18 Heterogeneous catalysts have many
advantages over their homogeneous counterparts. Generally
activity against human leukaemia cells.5
Derivative of acridine such as 5 (Fig. 3) was found to be the
most potent drug towards the metastatic breast cancer cells.6
⇑
Corresponding author. Tel.: +91 80 22961337; fax: +91 80 22961331.
E-mail address: m_af_pasha@ymail.com (M.A. Pasha).
http://dx.doi.org/10.1016/j.bmcl.2014.06.047
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

3908
K. B. Ramesh, M. A. Pasha / Bioorg. Med. Chem. Lett. 24 (2014) 3907–3913
O
heterogeneous catalysts are insoluble in common organic solvents,
O
N
cause low corrosion, and show environmental acceptability. Also,
the products can be easily separated from the reaction mixture
and the catalyst is recoverable, and we have prepared a new
heterogeneous catalyst-SiO2–I form silica through its chloride
and used successfully in the synthesis of acridines by a one-pot
four-component reaction. Due to our interest in the synthesis of
heterocyclic compounds,19–22 and in continuation of our previous
work on the application of reusable catalysts in organic reactions,23
we, herein, report a new and an efficient synthesis of some novel
and known 9-aryl-hexahydro-acridine-1,8-diones from two moles
of dimedone, one mole of benzaldehyde and one mole of
ammonium acetate as shown in the Scheme 1.
Br
N
X
R
R
R = secondary amine;
X = Cl, Br
R = secondary amine
We have found that, the prepared acridine analogues show
promising effect on cancer cell proliferation.
Figure 1.
Materials and methods: All chemicals were commercially avail-
able and used without further purification, except liquid aldehydes
which were distilled before use. All yields refer to isolated products
after purification. Products were characterized by the IR, 1HNMR,
13CNMR, Mass spectral and CHN analyses. Melting points were
measured on a Raaga, Indian make melting point apparatus. NMR
spectra were obtained on a 400 MHz and 100 MHz Bruker AMX
instruments in CDCl3 using TMS as a standard. ESI-MS analysis
was carried out using ESI-Q TOF instrument. Silica, silica chloride
and silica Iodide were characterised by SIRION high resolution
Scanning Electron Microscope–Energy Dispersive X-ray spectro-
scopic (SEM–EDX) technique.
N
N
CH2
CH2
Cl
Preparation of silica iodide: Silica gel (20 g) was suspended in
CH2Cl2 (50 mL), and SOCl2 (20 mL) was added drop wise with con-
tinuous stirring at 26 °C. Evolution of HCl and SO2 occurred instan-
taneously; after stirring for 1 h, the solvent was removed by
distillation; and the residual solvent was removed under reduced
pressure to get a dry solid of silica chloride (26.2 g). The solid
SiO2–Cl was washes with cold water and dried under vacuum.
NaI (3 g) was first dissolved in a mixture of EtOH–H2O (8:2,
10 mL), to this silica chloride (6 g) was added, mixed well and
filtered after 15 min, washed with cold water and dried under
vacuum to get SiO2–I (7.5 g).
Cl
O
O
O
O
3
4
Figure 2.
O
O
O
Detection of the iodide in silica iodide. Qualitative analysis. Test: 1.
To detect the presence of iodide in the catalyst, 0.25 mg of silica
iodide was transferred to a dry test tube; 0.25 mg of sodium metal
was then introduced and heated till the test tube turned red-hot.
After cooling the test tube, water (3 mL) was introduced and fil-
tered to get the sodium fusion extract (SFE). SFE (1.5 mL) was then
acidified with dil. HNO3 and treated with AgNO3 solution to get a
pale yellow precipitate which was insoluble in aqueous ammonia
to confirm the presence of iodide in the heterogeneous catalyst.24
Test: 2. SFE (1.5 mL) was acidified with dil. HCl, carbon tetra-
chloride (0.3 mL) was then added and treated with chlorine water
(1 mL) to get a violet globule which confirmed the presence of
iodide in the heterogeneous catalyst.
N
HN
NO2
O2N
Figure 3.
R
O
O
CHO
O
SiO2-I/EtOH
80 °C
2
+
NH4OAc
+
N
H
O
R
1
2
3
4a-k
Scheme 1. Synthesis of 9-aryl-hexahydro-acridine-1,8-diones.

K. B. Ramesh, M. A. Pasha / Bioorg. Med. Chem. Lett. 24 (2014) 3907–3913
3909
Figure 4. SEM–EDX of (a) silica, (b) silica chloride and (c) silica iodide.

3910
K. B. Ramesh, M. A. Pasha / Bioorg. Med. Chem. Lett. 24 (2014) 3907–3913
I-
O
H
O
Ar
Si
O
I-
Si
H
H
O
O
O
Ar
H
I
O
O
O
O
Ar
Ar
O
O
H2N
O
OH
Si I-
O
O
NH3
I-
Si
II
III
O
H
Ar
O
O
Ar
O
H
O
H
-H2O
N
H
N
H
OH
OH
I-
I-
Si
Si
V
IV
O
Ar
O
_
I
Si
O
O
O
=
I
Si I
Si
-H2O
N
H
Scheme 2. A plausible mechanism for the formation of acridines.
Table 1
Table 3
Effect of solvent on the synthesis of 9-phenyl-hexahydro-acridine-1,8-diones (4a)
Optimization of the amount of SiO2–I
Yielda (%)
Entry
Solvent
Temperature (°C)
Time (h)
Yielda (%)
Entry
SiO2–I (g)
Amount of NH4OAc (mmol)
Time (h)
1
2
3
4
5
6
7
CH3CN
H2O
MeOH
EtOH
CH2Cl2
THF
Solvent-free
83
98
65
80
40
68
70
5
5
4
3
6
5
6
45
55
50
60
1
2
3
4
5
6
7
8
9
0
2
2
2
2
2
2
2
2
2
8
15
10
2
2.5
2.5
2.5
2.5
2.5
40
50
55
60
70
90
90
90
90
0.01
0.05
0.06
0.08
0.10
0.15
0.20
0.25
Traceb
55
40
a
Isolated yield.
TLC.
b
a
Isolated yield.
Table 2
From the above mentioned tests it was ascertained that iodide
in present in silica iodide.
Influence of various catalysts on the synthesis of phenyl-hexahydro-acridine-1,8-
diones (4a)
Quantitative analysis. Test: 1. SiO2–I (1 g) was then taken in a
250 mL conical flask and titrated against 0.04 N Na2S2O3 and found
to have 0.33 milli-equivalent of iodide in it by the method devel-
oped by McDanlel.25,26
Test: 2 (SEM–EDX analysis). The SEM micrographs of silica and
silica based catalysts viz., chloride and iodide are shown in Figure 4.
SEM micrographs showed both chloride and iodide to have similar
texture and that the iodide and chloride in these materials is uni-
formly dispersed on silica surface and both can be used as hetero-
geneous catalysts Figure 4(b and c). Also, we have determined the
composition of the silica, silica chloride and silica iodide by EDX
studies. The EDX plots are shown in Figure 4 (a, b and c) along with
the SEM micrographs.
Entry
Catalysta
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
AmberliteIR120H
13
11
12
10
12
10
5
20
30
35
45
—
35
70
90
b
ZnCl2
CeCl3
b
b
K2CO3
NaIb
a
SiO2
SiO2–Cla
SiO2–Ia
2.5
a
b
c
0.1 g.
10 mol %.
Isolated yield.

K. B. Ramesh, M. A. Pasha / Bioorg. Med. Chem. Lett. 24 (2014) 3907–3913
3911
Table 4
SiO2–I catalyzed synthesis of acridines 4a–k in ethanol at 80 °C
Entry
Aldehydes
Producta
Time (h)
Yieldb (%)
Mp (°C)
Found
Reported
1
2
3
4
5
6
7
8
9
C6H5CHO
3-CNC6H4CHO
4-MeOC6H4CHO
4-ClC6H4CHO
4-NO2C6H4CHO
3-Br,4-MeOC6H3CHO
3-C2H5OC6H4CHO
5-F,2-HOC6H3CHO
2-HOC6H4CHO
4a
4b
4c
4d
4e
4f
4g
4h
4i
2.5
2.8
2.5
1.5
2
2
2.6
2
90
87
89
82
86
89
79
85
74
83
80
249–251
215–218
271–272
298–301
284–287
238–241
210–213
210–215
223–225
291–296
281–283
258–26028
—
270–27229
299–30130
286–28830
—
—
—
—
2.5
2.3
2
10
11
2,4-(CH3O)2C6H3CHO
4-(CH3)2NC6H4CHO
4j
4k
—
280–28231
a
Isolated yield. All the synthesized products were characterized from their spectroscopic analytical data (IR, NMR, CHN, ESI-MS), except 4a which was compared on TLC
with the authentic sample.
b
Isolated yield.
Novel compounds.
Mechanism:
A
probable mechanism for the formation of
We then started our work by examining the possibility of an
one-pot four-component reaction involving two molecules of
dimedone (1, Scheme 1), one molecule of benzaldehyde (2) and a
molecule of ammonium acetate (3) to get 9-phenyl-hexahydro-
acridine-1,8-dione (4a) in ethanol as a solvent in the presence of
SiO2–I.
A mixture of 1, 2, and 3 (Scheme 1) in 1.5 mL ethanol was stir-
red in the presence of SiO2–I for 2–3 h at 80 °C to get 4a in 90%
yield.27 Encouraged by this result, the reaction of various substi-
tuted arylaldehydes was taken up and the results of this study
are presented in the Table 4. The data presented in Table 4 indi-
cates that SiO2–I serves as an excellent catalyst for the synthesis
different substituted acridines in excellent yield in short reaction
duration.
Study on reusability of SiO2–I catalyst: With an effort to make the
present reaction much greener, the recovery and reusability of the
catalyst was studied. After the completion of the reaction, the solid
thus separated was filtered along with the catalyst. The residue
containing the catalyst was washed with ether to get the solid
SiO2–I which was then dried at 100 °C for 2 h and reused. The
results of the study of the reusability of the catalyst are presented
in the form of a graph in Figure 5. From Figure 5, it is clear that
SiO2–I can be used successively for at least four runs after the first
fresh run, after which the yield of the product dropped from 90% in
the first fresh run to 67% in the fifth run. The yield of 4a was found
to be 90%, 88%, 81%, 76% and 67%, respectively, for 1–5 cycles, the
marginal decrease of yield in the first five cycles may be due to loss
of the catalyst during the recovery.
acridines involves the activation of aldehyde followed the attack
of enol form of the dimedone to give the intermediate I. The inter-
mediate I may react with another molecule of dimedone to give II.
Attach of ammonia formed from ammonium acetate gives III, and
III may cyclise to give the acridine derivative IV which after the
elimination of a molecule of water may give V. In the last step V
may lose both the catalyst and another molecule of water to give
acridines as shown in the Scheme 2.
We studied the effect of several solvents like acetonitrile, water,
methanol, dichloromethane, and tetrahydrofuran on the reaction
of two moles of dimedone, one mole of benzaldehyde and one mole
of ammonium acetate. The reaction in tetrahydrofuran, water, ace-
tonitrile afforded the product but yields were poor. The best results
in terms of yield and reaction time were obtained with ethanol as a
solvent (Table 1, entry 4). We, then decided to investigate the effi-
cacy of SiO2–I for the synthesis of 4a under solvent-free condition
also, but, ended up getting the product in only 40% yield (entry 7).
We studied the effect of different catalysts such as
AmberliteIR120H, ZnCl2, CeCl3, K2CO3, NaI, SiO2, SiO2-Cl and
SiO2-I also on the preparation of 4a, and found that, SiO2-I is best
in terms of yield and duration of the reaction (Table 2, entry 8).
Further studies were carried out to optimize the amount of cat-
alyst by using different amounts of SiO2–I (0.06, 0.08, 0.10, 0.15,
0.20 and 0.25 g) and the results of this study are presented in the
Table 3. From this Table, it is clear that, 0.1 g of SiO2–I afforded
the product in 90% isolated yield (Table 3, entry 6). Increasing
the amount of catalyst did not improve the yield (entries 7–9).
Cell culture: HepG2 (Hepatocellular carcinoma cells) and MCF-7
(Human breast adenocarcinoma cells) cell lines were procured
from National Centre for Cell Sciences (NCCS), Pune, India. The cells
were cultured in minimum essential medium (MEM) growth med-
ium supplemented with 10% heat inactivated Fetal bovine serum
100
90
80
70
60
50
40
30
20
10
0
(FBS), penicillin (100 IU/mL), streptomycin (100
lg/mL) and
amphotericin-B (5 g/mL) in a humidified atmosphere of 5% CO2
l
at 37 °C until confluent. The cells were trypsinized with TPVG solu-
tion (0.2% trypsin, 0.02% EDTA, 0.05% glucose in PBS). The cultures
were grown in 25 cm2 flat bottles and the studies were carried out
in 96 wells plates.
MTT assay32: Cells were plated in 96 wells plate (1 ꢀ 104 cells/
well) and cultured for 24 h at 37 °C in 5% CO2 atmosphere to allow
cell adhesion. After 24 h, when partial monolayer was formed, cells
were treated with different concentration of standard drug (Doxo-
rubicin) and sample compounds for 48 h. Microscopic examination
was carried out and observations recorded every 24 h. After the
1
2
3
4
5
Number of Runs
Figure 5. Reusability of silica iodide in the synthesis of 4a.
treatment, the solutions in the wells were discarded and 50 lL of

3912
K. B. Ramesh, M. A. Pasha / Bioorg. Med. Chem. Lett. 24 (2014) 3907–3913
Table 5
References and notes
In vitro anticancer activity of acridine derivatives on HepG2 and MCF-7 human cancer
cell lines
1. Davoodnia, A.; Khojastehnezhad, A.; Tavakoli-Hoseini, N. Bull. Korean Chem. Soc.
2011, 32, 2243.
2. Hassankhani, A.; Maghsoodlou, M. T.; Habibi-Khorassani, S. M.; Hosseini-
Mahdiabad, H.; Marandi, G. ARKIVOC 2008, 2, 134.
Drug/
IC50value (
lg/mL) on HepG2
IC50 value (lg/mL)
formulation cells (Hepatocellular carcinoma
on MCF-7 cells (Human
breast adenocarcinoma
cells)
cells)
3. Paul, S.; Eelco, R.; Romanoorru, V. A. Med. Chem. Commun. 2012, 3, 1189.
4. Srikanth, G.; Rajesh Babu, Y.; Bhagavan Raju, M. World J. Pharm. Res. 2013, 2,
308.
5. Patel, M. M.; Mali, M. D.; Patel, S. K. Bioorg. Med. Chem. Lett. 2010, 20, 6324.
6. Alvala, M.; Bhatnagar, S.; Ravi, A.; Jeankumar, V. U.; Manjashetty, T. H.;
Yogeswari, P.; Sriram, D. Bioorg. Med. Chem. Lett. 2012, 22, 3256.
7. Niknam, K.; Damya, M. J. Chin. Chem. Soc. 2009, 56, 659.
8. Hajipour, A. R.; Ghayeb, Y.; Sheikhan, N.; Ruoho, A. E. Synlett 2010, 74.
9. Amini, M. M.; Fazaeli, Y.; Yassaee, Z.; Feizi, S.; Bazgir, A. Open J. Catal. 2009, 2,
40.
Doxorubicin 1.21 0.05
1.09 0.03
4.7 0.09
9.6 0.22
5.3 0.16
4.5 0.10
6.2 0.14
5.9 0.15
5.0 0.18
4b
4c
4f
4g
4h
4i
1.4 0.11
8.2 0.32
2.2 0.09
4.8 0.12
8.6 0.31
2.6 0.11
1.6 0.14
4j
10. Rashedian, F.; Saberi, D.; Niknam, K. J. Chin. Chem. Soc. 2010, 57, 998.
11. Ion, R. M.; Frackowiak, D.; Planner, A.; Wiktorowicz, K. Acta Biochim. Pol. 1998,
45, 833.
Active.
12. Poupelin, J. P.; Saint-Rut, G.; Foussard-Blanpin, O.; Narcisse, G.; Uchida-Ernouf,
G.; Lacroix, R. Eur. J. Med. Chem. 1978, 13, 67.
13. Jin, T. S.; Zhao, R. Q.; Li, T. S. ARKIVOC 2006, 11, 176.
14. Chandrasekhar, S.; Rao, Y. S.; Sreelakshmi, L.; Mahipal, B.; Reddy, C. R. Synthesis
2008, 17, 37.
15. Tu, S.; Miao, C.; Gao, Y.; Fang, F.; Zhuang, Q.; Feng, Y.; Shia, D. Synlett 2004, 255.
16. Venkatesan, K.; Pujari, S. S.; Srinivasan, K. V. Synth. Commun. 2009, 39, 228.
17. Das, B.; Thirupathi, P.; Mahender, I.; Saidi Reddy, V.; Rao, Y. K. J. Mol. Catal. A:
Chem. 2006, 247, 233.
freshly prepared MTT (2 mg/mL, prepared in PBS) was added to
each well. The plates were shaken gently and incubated for 3 h
at 37 °C in 5% CO2 atmosphere. The supernatant was removed
and the formazan crystals formed in the cells were solubilised by
18. Vahdat, S. M.; Baghery, S. Heterocycl. Lett. 2012, 2, 43.
19. Azzam, S. H. S.; Pasha, M. A. Tetrahedron Lett. 2012, 53, 6306.
20. Azzam, S. H. S.; Pasha, M. A. Tetrahedron Lett. 2012, 53, 7056.
21. Sudha, S.; Pasha, M. A. Ultrason. Sonochem. 2012, 19, 994.
22. Datta, B.; Pasha, M. A. Ultrason. Sonochem. 2012, 19, 725.
23. Sudha, S.; Datta, B.; Pasha, M. A. IJSTR 2013, 2, 54.
addition of 50 lL of iso-propanol. Finally, the absorbance was
recorded using a Micro-plate reader (Bio-Tek, ELX-800 MS) at a
wavelength of 540 nm.
control absorbance ꢁ test absorbance
%growth inhibition ¼
ꢀ 100
24. Dey, B. B.; Sitaraman, M. V.; Govindachari, T. R. Laboratory Manual of Organic
Chemistry; Allied Publishers Ltd.: New Delhi, 2000.
control absorbance
25. McDanlel, M. P. J. Phys. Chem. 1981, 85, 532.
The percentage growth was calculated using the standard for-
mula and IC50 values are shown in the Table 5.
26. Mendham, R. C.; Denny, J. D.; Barnes, M. J. K.; Thomas. Vogel’s Quantitative
Chemical Analysis; Prentice Hall: New York, 2000. 6th ed.
27. General procedure for the synthesis of 9-aryl-hexahydro-acridine-1,8-diones using
catalytic SiO2–I:
The data presented in the Table 5 shows the IC50 values obtain
by the treatment of the prepared acridines with the standard drug
(Doxorubicin) on HepG-2 and MCF-7 cells. It is clear from this
Table that, compounds 4b, 4f, 4i and 4j exhibit very good activity
towards HepG2 cell lines and 4b, 4f, 4g and 4j showed compara-
tively better activity towards MCF-7 cell lines.
In conclusion a reliable, practical procedure and an alternative
method for the synthesis of 9-aryl-hexahydro-acridine-1,8-diones
has been developed. The method involves the use of silica iodide,
a new heterogeneous catalyst which has made this method cost
effective, as the catalyst can be recycled for at least five runs with-
out loss of activity and the reaction involves simple workup proce-
dure. The compounds 4b, 4f, 4i and 4j exhibited very good activity
towards HepG2 cell lines and 4b, 4f, 4g and 4j showed compara-
tively better activity towards MCF-7 cell lines which can be a plen-
tiful source of potential anti-cancer drugs deserving further study.
In our opinion this method is superior to all other previously
reported methods33,34 of synthesis of 9-aryl-hexahydro-acridine-
1,8-diones.
A mixture of dimedone (2 mmol), aromatic aldehyde (1 mmol) and ammonium
acetate (1 mmol) was taken in ethanol (1.5 mL), mixed well and then SiO2–I
(0.1 g) was added. The reaction mixture was stirred at 80 °C for 2–3 h. The
course of the reaction was monitored on TLC (3:7::EtOAc/hexane). After
completion of the reaction, water (10 mL) was added and the separated solid
was filtered along with the catalyst. The residue was washed with ether and
the solid catalyst was recovered and kept aside for reuse. The crude product
thus obtained from the ether extract after the evaporation of ether was
subjected to silica gel column chromatography (3:7::EtOAc/light petrol) to get
the pure products.
Spectral and analytical data:
9-(30-Cyanophenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-acridine-1,8-
dione(4b):
Colorless solid, mp: 215–218 °C; IR (KBr,
m
cmꢁ1): 2240 (C–N), 3340 (N–H),
1710 (C@O); 1H NMR (400 MHz, CDCl3): d 1.10 (s, 6H, 2Me), 1.23 (s, 6H, 2Me),
2.40 (m, 8H, 4CH2), 5.49 (s, 1H, CH), 7.26–7.48 (m, 4H, Ar-H), 11.80 (s, 1H, N–
H); 13C NMR (400 MHz, CDCl3): d 27.9, 29.8, 31.9, 33.1, 46.8, 47.4, 77.1, 77.4,
77.8, 112.8, 115.1, 119.5, 129.4, 130.1, 131.0, 131.8, 140.4, 189.9, 191.4; ESI-
MS: [M+H] 375.7;
Anal. Calcd C24H26N2O2: C, 76.98; H, 7.00; N, 7.48; Found C, 75.34; H, 7.09; N,
8.29.
9-(40-Methoxyphenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-acridine-
1,8-dione (4c):
Colorless solid, mp: 271–272 °C; IR (KBr,
m H
cmꢁ1): 3320 (N–H), 1720 (C@O); 1
NMR (400 MHz, CDCl3): d 1.09 (s, 6H, 2Me), 1.22 (s, 6H, 2Me), 2.37 (m, 8H,
4CH2), 3.73 (s, 3H, OCH3), 5.48 (s, 1H, CH), 6.79 (dd, 2H, J = 8.0, 4.0 Hz, Ar-H),
6.98 (dd, 2H, J = 8.8, 0.8 Hz, Ar- H), 11.91 (s, 1H, N–H); 13C NMR (400 MHz,
CDCl3): d 27.81, 29.72, 30.11, 31.82, 32.46, 32.64, 41.29, 46.87, 47.51, 51.91,
55.54, 55.64, 113.90, 114.08, 116.23,128.23, 129.75, 130.26, 136.91, 158.02,
162.50, 189.80, 190.84, 196.94; ESI-MS: [M+Na] 400.2; Anal. Calcd C24H29NO3:
C, 75.96; H, 7.70; N, 3.69; Found C, 74.43; H, 7.10; N, 3.29.
Acknowledgments
Mr. Ramesh K.B. gratefully acknowledges the UGC, New Delhi
and the Bangalore University for a UGC-BSR fellowship. Authors
also acknowledge the financial assistance by the VGST, Dept. of
IT, BT and Science & Technology, Government of Karnataka for
the CESEM Award Grant No. 24 (2010-2011). We also thank Mr.
T.R. Lakshmeesha of Dept. of Microbiology, Bangalore University
for the biological assays of the prepared compounds.
9-(4’-Chlorophenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-acridine-1,8-
dione (4d):
Colorless solid, mp: 299–301 °C; IR (KBr,
m H
cmꢁ1): 3346 (N–H), 1734 (C@O); 1
NMR (400 MHz, CDCl3): d 1.09 (s, 6H, 2Me), 1.21 (s, 6H, 2Me), 2.18–2.48 (m,
8H, 4CH2), 5.47(s, 1H, CH), 6.99–7.26 (m, 5H, Ar-H), 11.87 (s, 1H, NH);
ESI-MS: [M+H] 384.3; Anal. Calcd C23H26ClNO2: C, 71.96; H, 6.83; N, 3.65;
Found C, 71.03; H, 7.02; N, 3.09.
9-(40-Nitrophenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-acridine-1,8-
dione (4e):
Supplementary data
Colorless solid, mp: 284–287 °C; IR (KBr,
m
cmꢁ1): 1550 (NO2), 3343 (N–H),
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.06.
047.
1716 (C@O); 1H NMR (400 MHz, CDCl3): d 1.12 (s, 6H, 2Me), 1.27 (s, 6H, 2Me),
2.31 (m, 8H, 4CH2), 5.54(s,1H,CH), 7.39 (dd, 2H, J = 12.4, 8.0 Hz, Ar-H), 8.00 (dd,
2H, J = 11.2, 11.2 Hz, Ar-H), 11.86 (s, 1H, N–H);

K. B. Ramesh, M. A. Pasha / Bioorg. Med. Chem. Lett. 24 (2014) 3907–3913
3913
ESI-MS: [M+H] 395.1;
Anal. Calcd C23H26N2O4: C, 70.03; H, 6.64; N, 7.10; Found C, 69.31; H, 6.09; N,
1789 (C@O); 1H NMR (400 MHz, CDCl3): d 0.99 (s, 6H, 2Me), 1.02 (s, 6H, 2Me),
2.33–2.58 (m, 8H, 4CH2) 2.62 (s, 1H, OH), 4.68 (s, 1H, CH), 6.99–7.18 (m, 4H, Ar-
H), 11.0 (s, 1H, N–H);
6.29.
9-(30-Bromo-40-methoxyphenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-
ESI-MS: [M+H] 366.1;
acridine-1,8-dione (4f):
Colorless solid, mp: 238–241 °C; IR (KBr,
NMR (400 MHz, CDCl3): d 0.93 (s, 6H, 2Me), 1.10 (s, 6H, 2Me), 2.09–2.52 (m,
8H, 4CH2), 3.79 (s, 3H, OMe), 4.78 (1H,CH), 6.71 (d, 1H, J = 8.8 Hz), 7.03 (s, 1H,
Ar-H), 7.27 (d, 1H, J = 2.4 Hz), 10.28 (s, 1H, NH);
ESI-MS: [M+H] 458.3;
Anal. Calcd C23H27NO3: C, 75.59; H, 7.45; N, 3.83; Found C, 75.43; H, 7.07; N,
3.20.
m H
cmꢁ1): 3369 (N–H), 1728 (C@O); 1
9-(20,40-Dimethoxyphenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-
acridine-1,8-dione (4j):
Colorless solid, mp: 291–296 °C; IR (KBr,
m H
cmꢁ1): 3330 (N–H), 1728 (C@O); 1
NMR (400 MHz, CDCl3) d 0.92 (s, 6H, 2Me), 1.09 (s, 6H, 2Me), 1.95–2.50 (m, 8H,
4CH2), 3.74 (s, 3H,OMe), 3.79 (s, 3H,OMe), 3.95 (s, 1H, NH), 4.73 (s, 1H, CH),
6.34 (d, 1H, J = 2.8 Hz, Ar-H), 6.45 (s, 1H, Ar-H), 6.85 (d, 1H, J = 8.4 Hz);
ESI-MS: [M+H] 410.2;
Anal. Calcd C24H28BrNO3: C, 62.88; H, 6.16; N, 3.06; Found C, 62.46; H, 6.19; N,
3.0.
9-(30-Ethoxyphenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-acridine-1,8-
dione (4g):
Anal. Calcd C25H31NO4: C, 73.32; H, 7.63; N, 3.42; Found C, 72.04; H, 7.00; N,
3.19.
Colorless solid, mp: 210–213 °C; IR (KBr,
m H
cmꢁ1): 3310 (N–H), 1724 (C@O); 1
NMR (400 MHz, CDCl3), d 1.05 (s, 6H, 2Me),1.16 (s, 6H, 2Me),1.32 (t, 3H,
J = 6.8 Hz) 1.95–2.50 (m, 8H, 4CH2), 3.31(s, 1H, NH), 4.01–4.03 (q, 2H,
J = 8.8 Hz), 4.84 (s, 1H, CH), 6.81(s, 1H, Ar-H), 6.83 (d, 1H, J = 8.4 Hz), 6.96(d,
1H, J = 7.2 Hz), 7.15 (t, 1H, J = 6.8 Hz);
9-(40-N,N-Dimethylaminophenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-
acridine-1,8-dione (4k):
Colorless solid, mp: 281–283 °C; IR (KBr,
m H
cmꢁ1): 3387 (N–H), 1756 (C@O); 1
NMR (400 MHz, CDCl3): d 1.08 (s, 6H, 2Me), 1.22 (s, 6H, 2Me), 2.31–2.44 (m,
8H, 4CH2), 3.80 [s, 6H, N(CH3)2], 5.54 (s, 1H, CH), 6.54–7.44 (m, 4H, Ar-H), 11.9
(s, 1H, N–H);
ESI-MS: [M+H] 393.2;
Anal. Calcd C25H32N2O2: C, 76.49; H, 8.22; N, 7.14; Found C, 75.72; H, 7.04; N,
6.29.
ESI-MS: [M+H] 394.2;
Anal. Calcd C25H31NO3: C, 76.30; H, 7.94; N, 3.56; Found C, 75.28; H, 7.09; N,
3.29.
9-(50-Fluoro-20-hydroxyphenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-
acridine-1,8-dione (4h):
Colorless solid, mp: 210–215 °C; IR (KBr,
m
cmꢁ1): 3400 (O–H), 3390 (N–H),
28. Srividya, N.; Ramamurthy, P.; Shanmugasundaram, P.; Ramakrishnan, V. T. J.
Org. Chem. 1996, 61, 5083.
29. Mora, A.; Suarez, M.; Ochoa, E.; Morales, A.; Del Bosque, J. R. J. Heterocycl. Chem.
1995, 32, 235.
30. Balalaie, S.; Chadegani, F.; Darviche, F.; Bijanzadeh, H. R. J. Chin. Chem. 1953,
2009, 27.
31. Singh, S. K.; Krishna, S. J. Heterocycl. Chem. 2011, 48, 69.
32. Denizot, F.; Lang, R. J. Immunol. Method 1986, 119, 203.
33. Mehul, M. P.; Mimansha, D. M.; Saurabh, K. P. Bioorg. Med. Chem. Lett. 2010, 20,
6324.
1725 (C@O); 1H NMR (400 MHz, CDCl3): d 0.99 (s, 6H, 2Me),1.12 (s, 6H, 2Me),
1.97–2.49 (m, 8H, 4CH2), 2.55(s, 1H, OH), 4.62 (s, 1H, CH), 6.68 (d, 1H,
J = 3.2 Hz, Ar-H), 6.81(d, 1H, J = 3.2 Hz, Ar-H), 6.96 (s, 1H, Ar-H) 10.48 (s, 1H, N–
H); 13C NMR (400 MHz, CDCl3): d 27.6, 28.18, 29.59, 31.40, 32.75, 41.98, 50.35,
111.43, 116.20, 118.75, 124.67, 125.04, 128.00, 128.42, 151.44, 169.64; ESI-
MS: [M+H] 384.3;
Anal. Calcd C23H26FNO3: C, 72.04; H, 6.83; N, 3.65; Found C, 71.62; H, 6.05; N,
3.21.
9-(20-Hydroxyphenyl)-3,3,6,6-tetramethyl-2,4,5,7,9,10-hexahydro-acridine-
1,8-dione (4i)
34. Mallika, A.; Shubhmita, B.; Alvala, R.; Variam, U. J.; Thimmappa, H. M.;
Perumal, Y.; Dharmarajan, S. Bioorg. Med. Chem. Lett. 2012, 22, 3256.
Colorless solid, mp: 223–225 °C; IR (KBr,
m
cmꢁ1): 3412 (O–H), 3356 (N–H),